Journal of Clinical Neuroscience xxx (xxxx) xxx

Contents lists available at ScienceDirect

Journal of Clinical Neuroscience

journal homepage: www.elsevier.com/locate/jocn

Review article

Neurological manifestations and complications of COVID-19: A literature

review
Imran Ahmad a, Farooq Azam Rathore b,⇑
a
Department of Neurology, Bahria University Medical and Dental College, Karachi, Pakistan
b
Department of Rehabilitation Medicine, Bahria University Medical and Dental College, Karachi, Pakistan

a r t i c l e i n f o a b s t r a c t

Article history: The Coronavirus disease due to SARS-CoV-2 emerged in Wuhan city, China in December 2019 and rapidly
Received 24 April 2020 spread to more than 200 countries as a global health pandemic. There are more than 3.5 million con-
Accepted 4 May 2020 firmed cases and around 165,000 to 243,000 fatalities. The primary manifestation is respiratory and car-
Available online xxxx
diac but neurological features are also being reported in the literature as case reports and case series. The
most common reported symptoms to include headache and dizziness followed by encephalopathy and
Keywords: delirium. Among the complications noted are Cerebrovascular accident, Guillian barre syndrome, acute
Neurology
transverse myelitis, and acute encephalitis. The most common peripheral manifestation was hyposmia.
Clinical features
Coronavirus
It is further noted that sometimes the neurological manifestations can precede the typical features like
Stroke fever and cough and later on typical manifestations develop in these patients. Hence a high index of sus-
Encephalitis picion is required for timely diagnosis and isolation of cases to prevent the spread in neurology wards.
Headache We present a narrative review of the neurological manifestations and complications of COVID-19. Our
Delirium aim is to update the neurologists and physicians working with suspected cases of COVID-19 about the
possible neurological presentations and the probable neurological complications resulting from this
novel virus infection.
Ó 2020 Elsevier Ltd. All rights reserved.

1. Introduction headache, dizziness, hypogeusia, and neuralgia) and complications

The Novel Coronavirus (COVID-19) outbreak originated from
the Wuhan city, China in December 2019 [1,2] Chinese authorities
reported unusual cases of pneumonia with an undetermined etiol-
ogy [3]. Initially all cases were clustered to the Huanan seafood
wholesale market. World Health Organization (WHO) declared it
a pandemic on 11 March 2020 [4]. As of 19th April 2020, there
are more than 2.3 million confirmed case of COVID-19 with
162,000 fatalities in the world [5].
COVID-19 has generated a great interest among physicians, sci-
entists, and researchers all around the globe [6]. The amount of
research and number of articles being published on COVID-19 is
unprecedented. It has been estimated that hundreds of manu-
scripts have been published on this topic since the start of the year
[7]. Data on different aspects of the disease manifestations, pathol-
ogy, transmission, prevention, and management strategies has
started emerging [8,9,10] Although COVID-19 preferentially affects
the respiratory and cardiovascular system, several patients of
COVID-19 are also likely to have neurological symptoms (such as
⇑ Corresponding author.
E-mail address: farooqrathore@gmail.com (F.A. Rathore).
including encephalopathy, acute cerebrovascular diseases,
impaired consciousness and skeletal muscular injury [11,12].
We present a narrative review of the neurological manifesta-
tions and complications of COVID-19. Our aim is to update the neu-
rologists and physicians working with suspected cases of COVID-
19 about the possible neurological presentations and the probable
neurological complications resulting from this novel virus
infection.
We searched Medline, PubMed Central and Google Scholar
using keywords ‘‘ COVID-19”, ‘‘Coronavirus”, ‘‘pandemic”, ‘‘SARS-
COV-2”, ‘‘neurology”, ‘‘neurological”, ‘‘complications” and ‘‘mani-
festations”. Search was limited only to English language manu-
scripts with no time limit. The literature search was last done on
11th April 2020. It is important to note that new data is being
shared regularly and so far, it consists mostly of pre-prints, case
reports, small case series, and part of an article describing clinical
features of COVID-19. Most of the data on COVID-19 at present is
being published from China [13]. At the time of writing this article
we were able to locate only 2 full text articles in English biomedical
literature specifically describing the neurological manifestations
and complications in COVID-19 in detail.

https://doi.org/10.1016/j.jocn.2020.05.017
0967-5868/Ó 2020 Elsevier Ltd. All rights reserved.

Please cite this article as: I. Ahmad and F. A. Rathore, Neurological manifestations and complications of COVID-19: A literature review, Journal of Clinical
Neuroscience, https://doi.org/10.1016/j.jocn.2020.05.017
2 I. Ahmad, F.A. Rathore / Journal of Clinical Neuroscience xxx (xxxx) xxx

2. Mechanism of CNS invasion Table 1

Comparison of Neurological complications and manifestations between the severely
ill Chinese and French patient series.
There is not enough experimental data available for COVID-19,
but it is considered a mutation of Severe Acute Respiratory Syn- Variable Mao et al. [11] Helms et al. [12]
drome Virus and Middle East Respiratory syndrome Virus [14]. Study design Retrospective Observational study
Therefore, it is expected that it will behave in a similar manner Chart review
Total Number of cases 214 58
[15]. Corona viruses are not primarily neurotropic virus and their
Number of seriously ill 88 58
primary target is respiratory epithelium. The target receptor for patients
attachment to cell and subsequent internalization is through the Median Age (Years) 58.7 63
angiotensin converting enzyme-2 receptor (ACE 2). After entry into Neurological Involvement 45.5% 84%
the cell the virus RNA is released in the cytoplasm subsequently Dizziness 19.3% NR
Headache 17.1% NR
translated and replicated, after formation of envelope protein and
Impaired consciousness 14.8% NR
incorporation of RNA into it the virus is released in the circulation Hypogeusia 5.6% NR
[16]. Hyposmia 5.1% NR
ACE 2 receptors are also found in glial cells in brain and spinal Skeletal muscle injury 19.3% NR
Simplified Acute Physiology NR 52
neurons. Hence it can attach, multiply and damage the neuronal
Score II
tissue. There is evidence from the animal experiments in mice that Agitation NR 40 (69%)
coronavirus enters the brain through a retrograde transfer via the Delirium as documented by NR 26 (65%)
olfactory epithelium or through the cribriform bone and reaches CAM-ICU
the brain in seven days’ time. Secondly, during the viremia phase Corticospinal tract signs NR 39 (67%)
Dysexecutive syndrome at NR 14 (36%)
of illness, disruption of blood brain barrier causes the virus to enter
discharge
the brain directly. Another postulated mechanism is the invasion of Ischemic stroke 5 (5.7%) 3/13 (23%)
peripheral nerve terminals by CoV which then gains entry to the Hemorrhagic Stroke 1 (1.13) Nil
CNS through the synapse connected route. Since COVID-19 has Leptomeningeal NR 8/13 (62)
enhancement on MRI
similarities with Severe Acute Respiratory Syndrome (SARS Cov),
EEG NR 1(8) diffuse bifrontal
therefore it can be presumed that it also follows the same path- slowing
ways for CNS invasion as discussed above. The detailed discussion
of host and virus interaction is beyond the scope of this article, and Foot Notes. CAM-ICU; Confusion assessment method in Intensive care unit, EEG;
electroencephalogram, MRI; Magnetic resonance imaging, NR; Not reported.
has been published elsewhere [15,16].

2.1. Neuropathological mechanism of CNS damage
COVID-19 results in neurological damage likely by two mecha-
nisms; hypoxic brain injury and an immune mediated damage to
the CNS.
2.1.1. Hypoxic brain injury
Severe pneumonia can result in systemic hypoxia leading to
brain damage. The contributory factors include peripheral vasodi-
latation, hypercarbia, hypoxia and anaerobic metabolism with
accumulation of toxic compounds. These can result in neuronal
swelling and brain edema which ultimately results in neurological
damage [9].
2.1.2. Immune mediated injury
Immune mediated injury is mainly due to the cytokine storms
with increased levels of inflammatory cytokines and activation of
T lymphocytes, macrophages, and endothelial cells. Further release
of Interleukins 6 causes vascular leakage, activation of complement
and coagulation cascade, disseminated intravascular coagulation
and end organ damage [17,18].
group had less typical symptoms of coronavirus like fever (40
[45.5%] Vs. 92 [73%],) and dry cough (30 [34.1%] Vs. 77 [61.1%],).
However, nervous system symptoms were significantly more com-
mon in severe cases as compared with non-severe cases (40
[45.5%] Vs. 38 [30.2%],). The most common CNS symptoms
reported were dizziness (36 [16.8%] and headache (28 [13.1%]).
The second article is a prospective case series of 58 patients
from France [12]. The median age of patients was 63 years and
neurological complications were seen in a higher percentage
49/58 (84%). As assessed by confusion Assessment method for
intensive care unit CAM-ICU scale, agitation was the most common
symptoms 40/58 (69%) followed by confusion 26/40 (65%).Corti-
cospinal tract signs were present in in 39/58 (67%)and a dysexecu-
tive syndrome at the time of discharge was noted in14/39 (36%).
Table 1 shows the comparison between the two study cohorts.
The neurological manifestations and complications of COVID-19
can be divided into central and peripheral as discussed below
Table 2.
Table 2
Neurological complications and manifestations of COVID-19.

Site Manifestations and Complications

3. Neurological manifestations of COVID-19 Central Nervous System Dizziness
Headache
The important neurological manifestations and complications Acute cerebrovascular disease
Impaired consciousness
of COVID-19 reported in literature so far are summarized in Table 1.
Transverse myelitis
There are 2 case series specifically describing neurological mani- Acute hemorrhagic necrotizing encephalopathy
festations and complications in COVID-19 patients. The first is a Encephalopathy
retrospective case series on neurological manifestation from China Encephalitis
by Mao et al. [11] They reported the patients in two groups. The Epilepsy
Ataxia
severely ill group had 88 (41.1%) patients while there were 126 Peripheral Nervous System Hypogeusia
(58.9%) patients in the non-severely ill group. Patients in the Hyposmia,
severely ill group were significantly older (58.2 ± 15 years Vs. 48. Neuralgia
9 ± 14.7 years) with more co-morbid conditions especially hyper- Guillian Barre syndrome
Skeletal muscle injury
tension (32 [36.4%] Vs. 19 [15.1%],). Surprisingly the severely ill

Please cite this article as: I. Ahmad and F. A. Rathore, Neurological manifestations and complications of COVID-19: A literature review, Journal of Clinical
Neuroscience, https://doi.org/10.1016/j.jocn.2020.05.017
 I. Ahmad, F.A. Rathore / Journal of Clinical Neuroscience xxx (xxxx) xxx
3.1. Central nervous system manifestations
3.1.1. Encephalopathy
Mao et al reported headache and encephalopathy in 40% of
patients in their cohort but the details and the diagnostic criteria
used was not described [11]. Filatove et al reported a case of a
74-year-old male with past medical history of atrial fibrillation,
stroke, Parkinson disease, chronic obstructive pulmonary disease,
and recent cellulitis, who presented to the emergency department
with fever and cough [19]. Initial diagnostic work up did not sug-
gest any serious issue and he was discharged to home. He reported
back with worsening symptoms, including headache, altered men-
tal status, fever, and cough. Chest X ray was suggestive of pneumo-
nia, while CT scan brain was unremarkable except for signs of
previous stroke. PCR assay of CSF was negative for infection. He
tested positive for COVID-19 and was intubated after developing
respiratory failure. He was started on hydroxychloroquine, lopina-
vir/ritonavir, and was continued on broad-spectrum antibiotics.
Chen et al. in a retrospective study of the clinical characteristics
of 113 COVID-19 patients from China, documented hypoxic
encephalopathy in 20 patients [20]. The incidence was significantly
lower in the patients who had recovered.
3.1.2. Acute hemorrhagic necrotizing encephalopathy (ANE)
Poyiadji and colleagues reported the first case of COVID-19–
associated acute hemorrhagic necrotizing encephalopathy (ANE)
from USA [21]. A female patient in her late fifties presented with
a 3-day history of cough, fever, and altered mental status. Poly-
merase chain reaction (PCR) assay was positive for COVID-19 and
negative for Herpes Simplex Virus 1 and 2, West Nile and Varicella
Zoster Virus. Non contrast head CT images demonstrated symmet-
ric hypoattenuation within the bilateral medial thalami with a nor-
mal CT angiogram and CT venogram. MRI brain demonstrated
hemorrhagic rim enhancing lesions within the bilateral thalami,
medial temporal lobes, and sub insular regions. She was started
on intravenous Immunoglobulin (IVIG), but the outcome was not
mentioned. ANE is a rare complication of viral infections like
influenza. The proposed mechanism is likely due to cytokine storm
which results in disruption of blood brain barrier and damage to
the brain parenchyma.
3.1.3. Acute myelitis
Kang Zhao et al reported acute myelitis in a 66-year-old male
form Wuhan city who presented with fever and body aches [22].
During the admission he developed acute flaccid paralysis of bilat-
eral lower limbs, sensory level at T-10 with urinary and bowel
incontinence. CT scan chest confirmed patchy pneumonia and
PCR for nasopharyngeal secretion was positive for COVID-19 infec-
tion. His serology for all other organism was negative.
He was treated empirically with IVIG, steroids, antibiotics and
antiviral. The response to treatment was good and he was dis-
charged to an isolation facility for further rehabilitation. The
authors attributed acute myelitis to the cytokine storm and overac-
tive inflammatory response as evident by high levels of serum fer-
ritin, C-reactive protein, Serum Amyloid-A and Interleukin-6 levels.
A major limitation of this case report is the lack of CSF PCR for coro-
navirus and MRI imaging of spine due to epidemic in Wuhan city.
3.1.4. Cerebrovascular accident
Sharifi et al from Iran reported case of intracranial bleed result-
ing in CVA in a 79 Years old COVID-19 positive male [23]. He was
admitted in the emergency in a semi-conscious state (Glasgow
Coma Scale 7/15) with history of fever and cough. On examination
there was, bilateral extensor planter response with coarse crepita-
tion in left lower zones. PCR assay from nasopharyngeal secretion
was positive for COVID-19. CT scan chest showed ground glass
Please cite this article as: I. Ahmad and F. A. Rathore, Neurological manifestations and complications of COVID-19: A literature review, Journal of Clinical
Neuroscience, https://doi.org/10.1016/j.jocn.2020.05.017
3
opacity suggestive of viral pneumonia. CT scan brain revealed a
massive bleed within the right hemisphere with intraventricular
and subarachnoid extension. This gentleman was neither a known
hypertensive nor on any anticoagulants that could have caused this
event. The platelets and PT/INR on admission were normal. The
authors postulated that probably dysregulation in the ACE 2 recep-
tors lead to cerebral auto regulation, sympatho-adreanl system and
cerebral blood flow could have resulted in the bleed. Another
aspect that is difficult to explain is the near normal blood pressure
in this case at the time of admission.
Mao and colleagues reported six case of CVA in their cohort of
214 [11]. There were five ischemic and one case of hemorrhagic
stroke. The French cohort had three cases of ischemic strokes
which were detected on neuroimaging when the patients under-
went imaging for encephlaophathy [12]. The patients did not have
focal neurological signs. Probably the symptoms were masked due
to presence of encephalopathy, but it highlights the importance of
neuroimaging in evaluation of such cases. However more evidence
is needed to establish a causal relationship between stroke and
COVID-19.
3.1.5. Encephalitis
Moriguchi et all reported first confirmed case of COVID-19 asso-
ciated viral encephalitis from Japan [24]. A 24 Years old man pre-
sented with fever followed by seizure and unconsciousness. He
had neck stiffness and underwent CT scan brain which was normal.
There was patchy pneumonia on CT chest. PCR assay from
nasopharyngeal swab was negative but CSF sample was positive
for COVID-19.The Diffusion weighted Images (DWI) showed hyper-
intensity along the wall of inferior horn of right lateral Ventricle.
Fluid-attenuated inversion recovery (FLAIR) images showed hyper-
intense signal changes in the right mesial temporal lobe and hip-
pocampus with slight hippocampal atrophy mainly on right
mesial lobe and hippocampus. There was no post Contrast
enhancement. The authors concluded that imaging findings were
suggestive of right lateral ventriculitis and encephalitis. This case
and presentation should alert clinicians regarding the neuro-
invasive potential of COVID-19 and encephalitis like presentation.
3.1.6. Headaches and dizziness
Headaches and dizziness are a nonspecific and minor symptoms
of many diseases. They have been reported as minor symptoms
associated with presentation of COVID-19 in different reports.
The incidence rages from 3 to 12.1% [25,26,27]. The detailed mech-
anism and pathophysiology has not been discussed in any of these
reports
3.2. Peripheral Nervous system manifestations and complications
3.2.1. Anosmia and chemosensory dysfunction
Yan et al from USA, documented chemosensory dysfunction in
59 COVID-19 positive and 203 COVID-19 negative patients from
a single center using an internet based cross sectional survey
[28]. They demonstrated that the smell and taste dysfunction
was higher in the COVID-19 positive cases as compared to the neg-
ative cases. (smell loss: 68% Vs. 16 % and taste loss: 71% Vs. 17%).
Most of the patients in this study were ambulatory, did not need
hospitalization and none required mechanical ventilation. They
theorized that probably in ambulatory COVID-19 patients virus
spreads via the nasal route as compared to the seriously ill patients
in which the spread is most likely pulmonary. Bagheri et al
reported results of a large Iranian cohort of 10,069 patients by
employing an online questionnaire-based survey [29]. Participants
were cases with problems in decreased sense of smell recently
(within the last 04 weeks of onset of COVID-19 outbreak in Iran).
Anosmia and hyposmia was reported by 48.23% of the respondents
4 I. Ahmad, F.A. Rathore / Journal of Clinical Neuroscience xxx (xxxx) xxx
while 83.38% also had a decreased taste sensation. The onset of
anosmia was sudden in 76.24%. Other clinical features reported
by the participants were flu or cold symptoms before anosmia
(75.5%), headaches (48.6%), nasal stiffness (43.7%) and fever
(37.3%). In contrast the study by Mao et al. in their cohort of 214
Chinese patients reported impairment of taste in 12 (5.6%) and
impairment of smell in 11 (5.1%) patients. Anosmia and taste dys-
function were not reported in the French cohort of COVID-19
patients.
3.2.2. Guillain barre syndrome (GBS)
So far eight cases of COVID-19 associated GBS have been
reported from China, Iran and Italy. Zhao et al reported the first
case of GBS in a 61 years old female who had travelled to Wuhan
City, China [30]. She presented with acute weakness in both legs
and severe fatigue, progressing within 1 day. Nerve Conduction
Studies (NCS) and Electromyography (EMG) were suggestive of
demyelinating polyneuropathy. She was treated with IVIG and
later on developed respiratory symptoms. She tested positive for
COVID-19. She infected two of her relatives and eight other people
including two neurologist and six nurses who were isolated but
were found negative for COVID-19. The author concluded that
based on the travel history, lymphopenia, and thrombocytopenia
at the time of admission are consistent with a Para-infectious pat-
tern of GBS due to COVID-19. She made a good motor recovery
after isolation and administration of anti-virals.
Sedaghat et al reported a 61 -Years old male with diabetes from
Iran [31]. He had cough, fever and sometimes dyspnea two weeks
before presenting with ascending paralysis leading to quadriplegia
and bilateral facial paralysis. NCS/EMG was suggestive of acute
motor sensoryaxonal neuropathy. He was managed with IVIG.
Authors have suggested that GBS should be considered as a neuro-
logical complication of COVID-19 since respiratory involvement is
common in COVID-19 and can be a risk factor for development of
GBS. Virani and colleagues reported GBS in a 54-Years male from
USA [32]. He presented with rapidly progressing ascending paraly-
sis leading to respiratory difficulty. There was no bladder or bowel
dysfunction. Reflexes were absent and MRI spine was normal. He
had history of diarrhea preceding the acute attack of weakness.
He tested positive for COVID-19. He was managed with IVIG and
anti-malarial. He responded well and was weaned off from the
ventilator. He was discharged to a rehabilitation facility for physi-
cal therapy.
Toscano et al reported five patients with GBS from Northern
Italy [33]. Lower-limb weakness and paresthesia were the main
presenting features in four patients, followed by facial weakness,
ataxia, and paresthesia in one patient. Four had positive PCR from
the nasopharyngeal swab on initial visit and fifth one was initially
negative but later turned positive. On NCS/EMG 02 patients had
features of demyelinating polyneuropathy while three had axonal
polyneuropathy. All the patients were treated with IVIG. It was
repeated in 02 patients and one patient had plasma exchange. After
one week, only one patient was able to ambulate independently
and discharged from the hospital. Further large scale studies are
required to prove this causal relationship between COVID-19 and
GBS.
3.2.3. Skeletal muscle damage
Mao et al reported skeletal muscle injury in 17 [19.3%] patients
in the severely ill and 6 [4.8%] patients in the non-severe group
[11]. They defined skeletal muscle injury as patient having myalgia
and elevated serum creatine kinase level above 200 U/L. They con-
cluded that it was not clear whether this was due to the direct
effect of virus on muscle tissue. The other possible mechanism pro-
posed was the infection-mediated immune response that causing
elevated pro-inflammatory cytokines in serum resulting in skeletal
Please cite this article as: I. Ahmad and F. A. Rathore, Neurological manifestations and complications of COVID-19: A literature review, Journal of Clinical
Neuroscience, https://doi.org/10.1016/j.jocn.2020.05.017
muscle damage. However, it is important to note that patients in
the severely ill group in addition to raised muscle enzymes, also
had elevated liver enzymes and deranged renal functions which
could have contributed to the this clinical picture. Moreover, no
specific diagnostic workup for confirmation like NCS/EMG or mus-
cle histopathology was performed. Therefore, it is difficult to
exclude that these patients might be having critical illness myopa-
thy and neuropathy in addition to skeletal muscle damage.
3.2.4. Other manifestations
Mao et al also reported neuralgia in five patients and epilepsy
and ataxia in one each, but further details were not mentioned
[11].
4. Conclusion
COVID-19 primarily affects the respiratory and cardiovascular
system. However, neurological involvement is not uncommon
and can result in serious complications if not detected and man-
aged early. These complications are mostly seen in severely ill
patients and in some cases can even precede the respiratory symp-
toms or many be the only symptoms in COVID-19 patients. There-
fore, a high index of suspicion is required while dealing with such
cases for prompt treatment and prevention. It is also important to
systematically collect data on the short and long term neurological
complications from different parts of the world and to document
the functional outcomes after these complications.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.jocn.2020.05.017.
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